Project 3: Nutrient Mediated Age-Related Changes In SDF-1 Results In Bone Loss. Aging triggers impaired localization, proliferation, survival, and differentiation of the main bone marrow stem cell populations, including bone marrow mesenchymal stromal/stem cells (BMSCs). A number of classical pathways involved in nutrient intake and nutrient response regulate BMSC survival and differentiation. We propose that at least two of these pathways are acting on bone homeostasis in significant part through regulation of the chemokine stromal cell-derived factor 1 (SDF-1, or CXCL12) and its major receptor CXCR4. There is evidence that the nutrient-regulated hormone, leptin, modulates SDF-1 and CXCR4 through insulin like growth factor 1 (lGF-1) and dipeptidyl peptidase IV (DPP4). We report that systemic and bone marrow cell expression of SDF-1 changes with age. We have recently shown, for the first time, that increasing leptin levels, which decline in aged mice, returns circulating SDF-1 levels in aged mice to levels seen in young mice. The expression of SDF-1-targeting microRNAs (miRNAs) is also altered in BMSCs from aged mice. These findings suggest the possibility that loss of function in aging BMSCs is linked to the dysregulated SDF-1 expression. We propose that nutrient effects on BMSCs and bone homeostasis are controlled in part through the SDF-1/CXCR4 pathway. We have further shown that SDF-1 increases BMSC engraftment and bone growth in a BMSC transplantation model. In this application we propose to test the hypotheses that: 1) BMSC CXCR4 and bone marrow levels of SDF-1 are critical to BMSC and osteoblast survival, differentiation and osteogenic function, and 2) Nutrient signaling through leptin/IGF-1 and dietary protein modulate BMSC expression and response to SDF-1/CXCR4. We will use novel transgenic mice (DPP4-/-), molecular tools (siRNA, miRNA vectors), and pharmacologic agents, and will work in coordination with the other program project Pis to test these hypotheses.